Hydroxycholanic acids



Patented Apr. 16, 1946 I HYDROXYCHOLANIC ACIDS Willard M. Hoelm, Kansas City, Mo., and Alexander W. Schneider, Kalamazoo, Mich" assirnors to George A.

Breon & Company, Kansas City, Mo., a corporation of Missouri No Drawing. Ori

ginal application October [1, 1940, Serial No. 360,137. Divided and this application August 4, 1944, Serial No. 548,143

4 Claims. (Cl. 260-39'Ll) after.

The invention accordingly comprises the ingredients and combinations of ingredients, the proportions thereof, steps and sequence of steps, and features of composition and synthesis, analysis, or metathesis, which will be exemplified in the products hereinafter described, and the scope of the application of which will be indicated in the following claims.

Accordingly the present invention relates to polyhydroxycholanic acids, that is, compounds oi the Caz-2o series, and more particularly to the conversion of these compounds into the corresponding mono and dihydroxycholanic acids, for example. The present invention is applicable, not only to the polyhydroxycholanic acids, such as cholic acids, but likewise to norcholanic, bisnorcholanic and etiocholanic acids. The starting materials of the present invention may be illustrated by the following formula:

' CH3 OH: R

where X and Y are hydrogen or hydroxyl groups,

- Where there are two or more such secondary hydroxyl groups present, limitation of the oxidizing agent used produces hydroxyketo rather than polyketo compounds. The oxidized products are 5 not isolated, but are convertedto semicarbazones,

or hydrazones Polysemicarbazones may be separated from monosemicarbazones by the ,diflerence in their solubility. The semicarbazones are then decomposed with alkalis at 170 to 200 C. to yield the monohydroxy or dihydroxycholanic acids. Thus, for example, lithocholic acids can be obtained in high yield from methyl cholate or from methyl desoxycholate.

Typical of the oxidizing agents-which may be used for converting the secondary hydroxyl group or groups to a keto group or groups, are chromic acid in acetic acid or in aqueous acetic acid solutions, aqueous acetic acid solutions of chromic acid in conjunction with an inert solvent, such as benzene, toluene, ether, chloroform, etc., po-

tassium dichromate and dilute sulfuric acid in conjunction with an inert solvent, and potassium permanganate with an inert solvent.

The semicarbazones are prepared by the use of semicarbazide hydrochloride in the presence of pyridine or sodium orpotassium acetate. Hydrazine hydrate is used to prepare the hydrazones if they are formed. Alkali which may be used for the decomposition of the semicarbazone or 0 hydrazone are, aqueous sodium or potassium hydroxide solutions; alcoholic sodium or potassium hydroxide solutions is a suitable alcohol such as methyl, ethyl, propyl, etc., alcohols: sodium alkoxide in a suitable alcohol, such as methyl, eth- 5 yl, propyl, isopropyl, butyl, etc. alcohols; and sodium benzyloxide.

Typical of the aroyLchlorides which may be used to convert the hydroxyl group on the 3- carbon atom to an acyl ester, are benzoyl ch10- 4o ride, tosyl chloride, o-benzoyl-benzoyl chloride,

etc.

The lithocholic acid obtained from methyl cholate or from methyl desoxycholate melts at N 184 to 185 0. and has The methyl bis-nor-desoxycholate, :by this The following examples are illustrative only of the present invention.

. Exmrtz 1 Lithocholic acid from cholic acid One thousand and fifty-five g. or methyl benzoxy-7,12-diketocholanate precipitates.

- C34H4aOsNs, 13.7%.

cholate are dissolved in benzene, and th benzene is partially removed in vacuo. Sufflcient dry benzene is added to make up the volume to 4 liters, and to this solution are added 214 ml. of anhydrous pyridine, and 311 ml. of benzoyl chloride. After standing over night the solid cake is triturated with water. The-benzene layer is washed well, first. with dilute acid, and then with dilute alkali, and finally with water. To this benzene solution is then added with stirring, a

' solution of 400 g. of chromic oxide in 1500 ml. of

water, and 1000 ml. of acetic acid. After the oxidation is completed, the benzene layer is washed well with water, ,and evaporated in vacuo. The residue is then taken up in 3 liters of methanol, and to this methanol solution is added a solution of 625 g. of semicarbazide hydrochloride in 500 -ml. of water, and 1000 mli of methanol. Upon refluxing the disemicarbazone of methyladuction of the disemicarbazone of methyl 3-benz-- oxy-7,l2-diketocholanate is 70 to 80 g. of material which melts at 184 to 185 0.; [a] +33i1.0 after two recrystallizations from acetone. From the reduction or the semicarbazone of methyl- 3-benzoxy-'7-keto-12-hydroxycholanate, there is obtained desoxycholic acid with a M. P. of 175.5- 176" (com), [oz] +56.8i0.6.

EXAMPLE 2 25 g. of the disemicarbazone of methyl S-benzoxy-7, 12-diketocholanate, prepared as outlined in Example 1, is reduced with a solution of 40 g. of potassium hydroxide in 200 ml. of methanol at 180 C. The lithoeholic acid purified by the method previously outlined, has .a M. P. of 185 (3., [u] +33 :1.0.

EXAMPLE 3 25 g. of the disemicarbazone of methyl 3-benzoxy-I, 12-diketocholanate prepared as outlined in Example 1, is reduced with asolution of 50 g.

' of sodium hydroxide in 250 ml. of water at 195 '0. i The lithocholic acid, purified by the method previously outlined,- melts at 184 to 185 C.,,

Examui 4 Bis-nor-lithocholic' acid from methyl bis-nor- .desoxychlolic acid. To a solution of 11 g. of

.rethyl bis-nor-desoxycholate is added 6 ml. of dry pyridine, and afterthis solution is cooled to 10 C 3.5 ml. of 'benzoyl chloride are added. 'I'hismixture is allowed to stand over night. and the benzene solution is then washed thorou hly with water, dilute hydrocholic acid, and then again with water. The benzene is removed and This the benzoylated ester is dissolved in 60 ml. of acetic acid. A solution of 5 g. of chromic acid in 40 m1. of 90% acetic acid solution is then added to the benzoylated ester, and after it is allowed to stand for ten minutes, sulfur dioxide is used to reduce the excess chromic acid present. The acetic acid is removed in vacuo, and the residue is extracted with water and ether. The ether solution is washed with dilute hydrochloric acid, dilute potassium hydroxidesolutlon, and finally with water. The ether is then removed, the residue is dissolved in 150 ml. of methanol. and a mixture of 6.3 g. of semicarbazide hydrochloride 6.0 g. of sodium acetate, 5 ml. of pyridine in ml. of methanol, and 15 m1. of water are'added.

' This mixture is refluxed for eight hours, the

methanol is then removed in vacuo, and the residue is suspended in hot water and filtered. After it is dried at 40 to 50 C. for ten hours, the semicarbazone of benzoxy-12-keto bis-nor-cholanate is obtained. This compound has a, melting point of 178-180 C. and upon analysis gave N, 7.74%. Calculated for C31H4305N3, 7.8 This material is heated four hours at 170 to 200 C. with ml. of 20% sodium methoxide. The bis-norlithocholic acid that is obtained after it is isolated by the above described procedure, melts at 218 to 220 C.

From the foregoing, it-willbe apparent that the present method is convenient for transformthrene carboxylic acid or its esters into the corresponding dihydroxy or monohydroxy compound.

In addition, the present method is adapted to large scale operation, and is carried out with a minimum isolation of intermediate products. Moreover, where a compoundhaving three or more hydroxyl groups is employed, variation in the amountof the oxidizing agent used produces corresponding variations in the percentages of the hydroxyketo and 'polyketo compounds that are obtained. The intermediates of thepresent invention are easily prepared from readily available materials and form desirable materials for the preparation of'the 'dihydroxy and monohydroxy compounds.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative andnot in a limiting sense. 7

We claim: i

1. .A compound selected from the group consisting of the disemicarbazone of methyl. S-benzoxy-7, 12-diketocholanate, the semicarbazone of methyl 3.- benzoxy-7-keto-12-hydroxycholanate,

)v 3. The semicarbazone. of methyl 3-benzoxy-7- keto-12-hydroxycholanate.

4. The semicarbazone of methyl 3-benzoxy-l2- keto bis-nor-cholanate.

HOEHN.

ALEXANDER W. SCHNEIDER- 

